Innate Immune responses play a critical role in the protection of organisms against pathogens. Innate immune responses are primarily triggered upon recognition of pathogen-associate molecular patterns (PAMP) by a class of evolutionary conserved receptors known as Toll-like receptors (TLRs). While other receptors, such as scavenger receptors on macrophages, also play important roles in innate immune responses, emerging knowledge strongly implicates Toll-receptors as the key molecules involved in this evolutionary ancient immune response. It is not surprising that microorganisms have evolved various strategies to evade the innate immune responses although our knowledge of such evasion mechanisms is still in a preliminary stage. Brucella abortus is a gram-negative intracellular bacterium that causes abortions in cattle and undulant fever, endocarditis, arthritis and osteomyelitis in humans. Because of the efficiency of aerosol infection and the lack of a human vaccine Brucella has been classified as a CDC/NIAID category 2 biological warfare agent. In an attempt to understand possible mechanisms used by Brucella to subvert innate immune responses, we have identified a novel protein encoded in the Brucella genome that is highly homologous to the mammalian TIR (Toll/IL-R) domain, that we have named TIRB (TIR-domain protein of Brucella). We have cloned this gene and have shown that its over-expression in mammalian cells leads to inhibition of signaling through Toll-receptors. We hypothesize that expression of TIRB by Brucella is a means to suppress host innate immune responses and may help explain the pathogenicity and infectivity of Brucella. We are therefore proposing to characterize the role of TIRB in Brucella infection and we believe that our studies will help in the future development of therapeutic strategies, including vaccination, against human infection by Brucella.